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Tetrahedron 70 (2014) 2654e2660

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Tetrahedron

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Study of chemoselective asymmetric hydrogenation of (1-bromo-1-alkenyl)boronic esters with iridiumeP̂ N complexes

Stephen J. Roseblade a, Ivana Gazi�c Smilovi�c b, Zdenko �Casar b,c,d,*a Johnson Matthey, Catalysis and Chiral Technologies, Unit 28, Cambridge Science Park, Milton Road, Cambridge CB4 0FP, UKb Lek Pharmaceuticals, d.d., Sandoz Development Center Slovenia, API Development, Organic Synthesis Department, Kolodvorska 27, SI-1234 Menge�s,Sloveniac Sandoz GmbH, Global Portfolio Management API, 6250 Kundl, Austriad Faculty of Pharmacy, University of Ljubljana, A�sker�ceva cesta 7, SI-1000 Ljubljana, Slovenia

a r t i c l e i n f o

Article history:Received 20 December 2013Received in revised form 13 February 2014Accepted 24 February 2014Available online 3 March 2014

Keywords:HydrogenationCatalysisChemoselectivityEnantioselectivityP̂ N Ir complexesDrugs

* Corresponding author. Tel.: þ43 5338 200 3747; faaddress: zdenko.casar@sandoz.com (Z. �Casar).

0040-4020/$ e see front matter � 2014 Elsevier Ltd.http://dx.doi.org/10.1016/j.tet.2014.02.065

a b s t r a c t

In this paper we report the first chemoselective asymmetric hydrogenation of (1-bromo-1-alkenyl)bo-ronic esters, which constitutes a new route to (a-bromoalkyl)boronic esters. The study demonstrates thatexcellent chemoselectivities along with full conversions can be obtained for hydrogenation of alkylsubstituted derivatives with iridiumeP̂ N complexes. Moreover, acyclic alkyl derivatives afford (a-bro-moalkyl)boronic esters in good enantioselectivities ranging from 64 to 73% ee. A cyclic alkyl derivativewas obtained only in a nearly racemic form. The (1-bromo-1-alkenyl)boronic esters appear to be lessreactive towards homogenous hydrogenation conditions than their chloro analogues as demonstrated bythe higher catalyst loadings required to achieve full conversions for alkyl derivatives and lower con-versions observed for the aryl substituted derivatives.

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1. Introduction

(a-Haloalkyl)boronic esters represent an important class ofchiral building blocks useful for the synthesis of complex chiralcompounds.1 Their efficient asymmetric synthesis, via break-through and unique homologation methodology, was elaborated inthe early 1980s by Matteson.1 Furthermore, beside their syntheticvalue, these compounds proved to be ideal and till recently the onlyprecursors for the preparation of a-amino boronic acids,2 whichwere found to be the key constituent of some proteasome in-hibitors.3,4 These active substances demonstrated a real therapeuticpotential as evidenced by marketing authorizations obtained forbortezomib5,6 as an anti-cancer treatment both in US and EU at thebeginning of the last decade. This has triggered further interest inthese compounds and new refined drug candidates entered theclinical studies among which ixazomib7 and delanzomibe8 are inthe most advanced stage. Moreover, a-amino boronic acid moietyproved to be a key structural element in the dipeptidyl peptidase-4(DPP-4) inhibitors, such as dutogliptin for treatment of type 2 di-abetes mellitus (Fig. 1).9 Although, chiral (a-chloroalkyl)boronic

Fig. 1. Structure of drugs and drug candidates containing a-amino boronic acid moiety.

x: þ43 5338 200 418; e-mail

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Scheme 2. Chemoselective asymmetric hydrogenation of (1-bromo-1-alkenyl)boronicesters with IreP N̂ complexes.

S.J. Roseblade et al. / Tetrahedron 70 (2014) 2654e2660 2655

esters were extensively investigated by Matteson, preparation oftheir bromo analogues is much less explored.1 Indeed, while theracemic (a-bromoalkyl)boronic esters were obtained by severalmethods, such as addition of liquid HBr to a,b-unsaturated boronicesters precursors,10 mercuration and bromination of 1,1-bis(ethylenedioxyboryl)-2-phenylethane,11 racemic homologationmethodology with (dibromomethyl)lithium,12 hydrozirconationand NBS bromination of alkenyl boronic esters,13 their chiralcounterparts were prepared infrequently only via Matteson’sasymmetric homologation methodology using (dibromomethyl)lithium in the presence of ZnCl2.14

Recently, in our preliminary communication we have elaboratedthe first alternative route to (a-chloroalkyl)boronic esters via che-moselective asymmetric hydrogenation of (1-chloro-1-alkenyl)bo-ronic esters with iridiumeP N̂ complexes.15 We were thereforeprompted to extend the scope of our method and to investigate thehomogenous hydrogenation of (1-bromo-1-alkenyl)boronic esterswith two clear objectives in mind. Firstly, it would be desirable tohave access to (a-bromoalkyl)boronic esters as a valuable alternativeto (a-chloroalkyl)boronic ester, sincebromine is a significantly betterleaving group compared to chlorine, which provides an advanta-geous option in the substitution reactions with poor and/or un-charged nucleophiles. Namely, it is known that epimerization of thea-carbon in (a-haloalkyl)boronic ester occurs in the presence of freehalide ion.16 This is not problematic when substitution is carried outwith strong nucleophiles, which provide significantly higher sub-stitution rate for the primary reaction compared to the reactionwithliberated free halide byproduct originating from the primary re-action. However, whenweak nucleophiles are used (e.g., azide ions)the rate of the primary reaction is comparable to the rate of the re-actionwith free halide byproduct originating from primary reaction,which could lead to a significant extent of epimerization.16,17 More-over, (a-bromoalkyl)boronic esters provided superior reactivity andafforded better yields compared to their chloro analogues in reactionwith nucleophiles like enolates12 and alkoxides.18 Secondly, ho-mogenous hydrogenation of (1-bromo-1-alkenyl)boronic estersmight provide additional insight into the unique nature of the ac-tivity and selectivity of P N̂eIr complexes on halovinyl substratesbearing a boronmoiety. Therefore, itwould be interesting to observe,if the high chemoselectivity of C]C hydrogenation versus CeBrhydrogenolysis could be preserved with bromo derivativeswhere carbonehalogen bond strength is notably lower (for ca.10e12 kcal/mol) compared to the chloro derivatives.19 Indeed, it isperceived that the extent of dehalogenation in homogenously cata-lyzed hydrogenation essentially depends on the strength of the CeXbond.20

2. Results and discussion

Our investigation began with the preparation of suitable vinylbromide substrates bearing the boron moiety for the exploration ofhomogenous hydrogenation reactions. The desired (1-bromo-1-alkenyl)boronic esters 2aeg were readily prepared according toSrebnik’s method21 by the treatment of easily accessible alky-nylboronates 1aeg15a with Schwartz’s reagent (Cp2Zr(H)Cl),22 fol-lowed by addition of NBS (Scheme 1). The pure boronic esters 2aeg

Scheme 1. Synthesis of (1-bromo-1-alkenyl)boronic esters 2. Reagents and conditions:(i) Cp2Zr(H)Cl, THF, rt 1 h; (ii) NBS, rt, 1 h.

were isolated in 32e67% yield for non-optimized conditions exceptin the case of 2b, which was obtained as an inseparable 2:1 mixtureof regioisomers with 2-bromovinyl boronic ester and was used assuch in the hydrogenation experiments.

With (1-bromo-1-alkenyl)boronic esters 2aeg in hand, wecontinued our investigation with the screening for the best per-forming hydrogenation catalyst. A variety of different catalystsbased on combinations of P P̂, N N̂ and P N̂ ligands with variousRh, Ru and Ir metal precursors were screened for homogenoushydrogenation using 2a as a model substrate. We investigated thehydrogenation of 2a using a defined range of transition metalcomplexes. Using Rh and Ru complexes low conversion was ob-tained and in two cases using Ru-phosphine complexes the de-bromination product 4a was formed. Interestingly, as in the caseof chloro analogues,15 unique reactivity of P N̂eIr catalysts23 wasobserved regarding the chemoselectivity of C]C hydrogenationversus CeBr hydrogenolysis. Indeed, the only useful results wereobtained with this class of catalysts based on pyridylphosphine li-gands L2 and L3,24 phosphiniteeoxazoline ligands L4 (SimplePHOX)25 and L8 (ThrePHOX),26 phosphanyl oxazolines L5 and L6,27

chiral spiro phosphineeoxazoline ligand L728 and NeoPHOX ligandL929 (Scheme 2, Fig. 2, see Supplementary data for detailedscreening data).

Fig. 2. Structure of the key ligands used in catalysts for asymmetric hydrogenation of(1-bromo-1-alkenyl)boronic esters.

S.J. Roseblade et al. / Tetrahedron 70 (2014) 2654e26602656

Surprisingly, hydrogenation using Crabtree’s catalysts [Ir(P-Cy3)(Py)(COD)]PF6 gave very low conversion of 2a to the desiredreaction product 3a (see Supplementary data for detailed data).This is in contrast to the analogous chloro derivative that gave goodconversion using Crabtree’s catalyst at extended reaction times.15

Following on from the successful application of IreP N̂ complexesto the asymmetric hydrogenation of (1-chloro-1-alkenyl)boronicesters15 a wide range of IreP N̂ complexes was tested in the hy-drogenation of 2a. The complex bearing a ferrocenyl imidazolineligand L1a that proved to be reactive and highly enantioselective inthe hydrogenation of (1-chloro-1-alkenyl)boronic esters15 wasfound to be quite unreactive and unselective in the hydrogenationof 2a (Table 1, entry 1). A variety of related complexes was testedand higher conversions were obtained using phosphiniteeoxazo-

Table 1Hydrogenation of 2a with IreP N̂ complexesa

Entry Catalyst Conv. (%)b 3a (%)b 4a (%)b ee (%)b

1 [Ir(COD)(L1a)]BArF 15 5 10 nd2 [Ir(COD)(L2)]BArF >99 94 6 32 (e2, þ)3 [Ir(COD)(L3)]BArF >99 94 6 14 (e2, þ)4 [Ir(COD)(L4)]BArF >99 92 7 05 [Ir(COD)(L5)]BArF >99 95 5 16 (e1, e)6 [Ir(COD)(L6)]BArF >99 95 5 10 (e1, e)7 [Ir(COD)(L7)]BArF >99 97 3 37 (e1, e)8 [Ir(COD)(L8b)]BArF >99 92 (70)c 8 60 (e1, e)9 [Ir(COD)(L9)]BArF 97 89 8 73 (e2, þ)

nd¼not determined.a Standard reaction conditions: 10 mol % of catalyst, CH2Cl2, 50 �C, 30 bar H2, 18 h.b Conversions, yields and enantiomeric excesses calculated by GC analysis

on DexCB GC column (see Supplementary data for detailed screening data).c The highest isolated yield on 0.1 mmol scale.

line and phosphino-oxazoline complexes. Two complexes bearingpyridineephosphinite ligands (L2 and L3)24 gave full conversionwith only 6% de-brominated side-product 4a formed (Table 1, en-tries 2 and 3). The enantiomeric excess of the reaction product 3awas low in both cases (14e32%). The phosphiniteeoxazolinecomplex bearing a SimplePHOX ligand L4,25 also gave full conver-sion with a low level of de-bromination, but the product formedwas racemic (Table 1, entry 4). Other complexes were tested in thescreening and a fewgave high conversion to the desired product 3a.The catalysts based on phosphino-oxazoline ligands L5 and L6,developed by Mazet, Burgess and Pfaltz groups,27 were tested andgave high conversion albeit with low enantiomeric excess (Table 1,entries 5 and 6). The catalyst incorporating the spirocyclicphosphino-oxazoline ligand L728 also gave high conversion to 3a,with a low level of de-bromination (3% of 4a). Disappointingly, theee of the product was low (37%, Table 1, entry 7). Higher enantio-selectivity was observed using the phosphiniteeoxazoline complexL8b,26 bearing a PCy2 co-ordinating group. In this case, a full con-version of starting 2a took place, with 92% conversion to the desiredproduct 3a, which was formed in 60% ee, along with 8% de-brominated side-product 4a. After the filtration over silica geleluting with isohexane/EtOAc (20:1), 3a was isolated repeatedly in65e70% yield (Table 1, entry 8). The catalyst based on phosphino-oxazoline ligand L9, NeoPhox, developed by Pfaltz et al.,29 wasalso tested and gave high (97%) conversion of 2a and 89% of desiredproduct 3awith a good ee of 73% and only 8% of 4a formed (Table 1,entry 9).

These results demonstrate the lower reactivity of (1-bromo-1-alkenyl)boronic ester 2a compared to its (1-chloro-1-alkenyl)bo-ronic ester analogue.15 Gratifyingly, certain Ire(P̂ N) complexesidentified in the screening process have given complete conversionand high yield of the desired hydrogenation product 3a, with ex-cellent chemoselectivity and relatively low levels of de-brominationranging from 3 to 10%. The enantioselectivities observed variedwidely from very low to quite good, with good enantioselectivitiesobtained in range of 60e73% ee in two cases (Table 1, entries 8 and9).

To evaluate the reaction scope, a variety of aliphatic derivativeswas also investigated (Table 2). The first scope extension substratewas a vinylic derivative 2b (Table 2, entries 1e4). The Crabtree’scatalyst gave modest conversion (see Supplementary data for de-tailed data), but three IreP N̂ complexes bearing a phosphinite co-ordinating group were found to give high conversion to the desiredproduct with a relatively low level of de-bromination (5e13% of4b). The enantiomeric excesses for this substrate were similar tothose obtained with the initial substrate 2a: the complex bearingligand L8b gave 67% ee at full conversion and allowed us to isolate3b in moderate 50% yield after flash chromatography over silica gel(isohexane/EtOAc¼20:1), due to the high volatility of the product(Table 2, entry 3). The pyridine phosphinite ligand L2 gave 40% eeand the SimplePHOX ligand L4 gave 24% ee, respectively.

The next example in this series was the substrate 2c (Table 2,entries 5e10). The catalyst screening showed again that the complexbased on L1b has low reactivity. For this substrate full conversionwas obtained using the pyridineephosphinite ligand L2, which gave89% of the desired product in 43% ee. Full conversion was also ob-tained using ligand L8b, to give 3c with 64% ee and only 9% of thede-brominated side-product 4c. In this case 3c was isolated in65e70% yield in several repeated experiments (Table 2, entry 8).Surprisingly, ligand L9 did not give high conversion in this case.

Substrate 2d (Table 2, entries 11e16), bearing an n-propyl sub-stituent on the C]C double-bond was tested in the hydrogenationusing IreP N̂ complexes and gave similar results to substrate 2c:the complex incorporating L2 gave full conversion to the desiredproduct with 40% ee. Complex based on L8b gave full conversion togive the desired product 3d with 64% ee and the same isolatedyields as in the case of compound 3c (Table 2, entry 14). Theseresults show a consistency in the method and demonstrate thatacyclic aliphatic substrates are suitable for this transformation.

Substrate 2e (Table 2, entries 17e20), bearing a cyclohexylsubstituent was prepared and tested in the hydrogenation reaction.Although high conversion resulted using several of the IreP N̂complexes to give the desired product 3e with good chemo-selectivity, the product enantiomeric excesses were low in all cases(see Supplementary data for additional examples). Nevertheless,nearly racemic 3e was isolated reproducibly in 65e70% yield afterstandard isolation procedure (Table 2, entry 17).

Aromatic substituents have also been screened to further probethe scope of this hydrogenation reaction with IreP N̂ catalysts.Substrate 2f (Table 2, entry 21), bearing a phenyl group, was madeand tested in hydrogenations using a variety of complexes. It wasfound to be very unreactive, giving<20% conversion in most cases(10 mol %, 50 �C, 30 bar H2, 18 h). The only catalyst to give >50%conversion was that incorporating the pyridine phosphinite ligandL2 that gave 64% conversion resulting in 34% hydrogenationproduct 3f and 30 de-bromination side-product 4f according to GCanalysis and LC-HRMS analysis of the reaction mixture. The ee ofthe product was 44%, in-line with previous results from hydroge-nation of the acyclic aliphatic substrates using this catalyst. Sub-strate 2g (Table 2, entry 22), bearing a p-F-phenyl substituentgave a similar result: 56% conversion with the complex bearingL2 to give 30% hydrogenation product and 26% de-brominatedside-product 4g. The ee of 3g was 34%. Other catalysts proved tobe much less reactive.

Table 2Hydrogenation of (1-bromo-1-alkenyl)boronic esters 2beg with IreP N̂ complexesa

Entry Substrate 2 Catalyst Conversion (%)b Product 3 3 (%)b ee (%)b 4 4 (%)b

1c 2b (R3¼H) [Ir(COD)(L2)]BArF >99 3b 78 40 (e2, þ) 4b 132c 2b (R3¼H) [Ir(COD)(L4)]BArF >99 3b 76 24 (e1, e) 4b 123c 2b (R3¼H) [Ir(COD)(L8b)]BArF >99 3b 86 (50)d 67 (e1, e) 4b 54c 2b (R3¼H) [Ir(COD)(L8a)]BArF 54 3b 38 29 (e1, e) 4b 135 2c (R3¼Me) [Ir(COD)(L1b)]BArF 13 3c 0 nd 4c 136 2c (R3¼Me) [Ir(COD)(L2)]BArF >99 3c 89 43 (e2, þ) 4c 117 2c (R3¼Me) [Ir(COD)(L4)]BArF 40 3c 22 48 (e1, e) 4c 158 2c (R3¼Me) [Ir(COD)(L8b)]BArF >99 3c 91 (65-70)d 64 (e1, e) 4c 99 2c (R3¼Me) [Ir(COD)(L8a)]BArF 39 3c 23 30 (e1, e) 4c 1110 2c (R3¼Me) [Ir(COD)(L9)]BArF 26 3c 14 54 (e2, þ) 4c 1211 2d (R3¼n-Pr) [Ir(COD)(L1b)]BArF 20 3d 7 nd 4d 912 2d (R3¼n-Pr) [Ir(COD)(L2)]BArF >99 3d 92 40 (e2, þ) 4d 813 2d (R3¼n-Pr) [Ir(COD)(L4)]BArF 30 3d 15 20 (e2, þ) 4d 1514 2d (R3¼n-Pr) [Ir(COD)(L8b)]BArF >99 3d 94 (65e70)d 64 (e1, e) 4d 615 2d (R3¼n-Pr) [Ir(COD)(L8a)]BArF 24 3d 12 nd 4d 1216 2d (R3¼n-Pr) [Ir(COD)(L9)]BArF 29 3d 16 nd 4d 1317 2e (R3¼Cy) [Ir(COD)(L2)]BArF 95 3e 88 (65-70)d 2 (e1, þ) 4e 719 2e (R3¼Cy) [Ir(COD)(L4)]BArF 82 3e 75 6 (e2, e) 4e 719 2e (R3¼Cy) [Ir(COD)(L8a)]BArF 27 3e 15 nd 4e 820 2e (R3¼Cy) [Ir(COD)(L8b)]BArF 58 3e 52 0 4e 621e 2f (R3¼Ph) [Ir(COD)(L2)]BArF 64 3f 34 44 (e2, þ) 4f 3022e 2g (R3¼p-FePh) [Ir(COD)(L2)]BArF 56 3g 30 34 (e2, þ) 4g 26

nd¼not determined.a Standard reaction conditions: 10 mol % of catalyst, CH2Cl2, 50 �C, 30 bar H2, 18 h.b Conversions, yields and enantiomeric excesses calculated by GC analysis. Reactions with 2beg analyzed on DexCB GC column for conversions and yields. Enantiomeric

excesses for 2b, 2c, 2d, 2f and 2g determined on DexCB GC column and for 2e on GammaDex 225 GC column (see Supplementary data for full details).c 2:1 mixture of 2b and 2-bromovinyl boronic ester were used under the same conditions as noted above. Conversions, yields and enantiomeric excesses calculated by GC

analysis and are based on the content of the pure 2b in the substrate.d Range of isolated yields for several repeated experiments on 0.1 mmol scale.e Results determined based only on GC and HRMS analysis of the reaction mixture (see Supplementary data for full details).

S.J. Roseblade et al. / Tetrahedron 70 (2014) 2654e2660 2657

These results clearly indicate that the hydrogenation of (1-bromo-1-alkenyl)boronic esters 2 is more difficult than in the caseof their (1-chloro-1-alkenyl)boronic ester analogues,15 due to thelower reactivity. Interestingly, based on the 13C NMR shifts for b-carbon atoms in compounds 2, the C]C bond appears to be morepolarized in the caseof compounds2 than in their chloro analogues15

(see Supplementary data fordetailed data),which demonstrates thatthe presence of less electronegative bromine in the structure en-hances the effect of C]C bond polarization in boronate esters due toBeC p-bonding.30 Furthermore, it is known that polarization ofdouble-bond can influence the outcome of the hydrogenation withIreP N̂ complexes.23k,31 Therefore, the electronic effects (e.g., en-hanced bond polarization) as well as the steric effects (e.g., higherbulk of bromine atom), can influence the energy of transition statesassociated with hydride addition to C]C bond.23k,31 Evidently, theinterplay of steric and electronic effects in compounds 2 leads toenergetically less favourable transition states, which render thesecompounds less reactive towards IreP N̂ complexes catalyzed hy-drogenation compared to their chloro analogues. Surprisingly, de-spite a lower CeX bond strength in compounds 2 compared to theirchloro analogues, high chemoselectivities could be attained withonly 5e9% of 4 formed.20 Whilst the scope of the asymmetric hy-drogenation reaction investigated is limited to aliphatic substituted(1-bromo-1-alkenyl)boronic esters, the range of ligands that areuseful for this transformation is quite diverse. They include phos-phiniteeoxazoline, phosphinite pyridine and phosphino-oxazolineligands. The highest activity has been observed with the phosphin-ite pyridine ligand L2, but higher enantioselectivities have been ob-tained using the phosphinite oxazoline L8b and phosphino-oxazoline L9. Importantly, as in the case of chloro derivatives the

use of IreP̂ N hydrogenation catalysts has allowed chemoselectivehydrogenation, giving low levels of de-halogenated side-products 4.

3. Conclusion

Our study demonstrates that homogenous asymmetric hydro-genation of (1-bromo-1-alkenyl)boronic esters with selectediridiumeP N̂ complexes can be achieved with excellent chemo-selectivity and full conversion for alkyl substituted derivatives.Good enantioselectivities ranging from 64 to 73% ee are obtainedfor acyclic alkyl derivatives, while the cyclic alkyl derivative didn’tallow any stereoselection and was obtained practically in a racemicform only. Hydrogenation of aryl substituted (1-bromo-1-alkenyl)boronic esters turned out to be a difficult task due to their lowreactivity in the hydrogenation reaction, which was evidenced bythe low conversions obtained in these examples. The presentedapproach provides the only alternative to Matteson’s methodologyfor the synthesis of this rarely described and useful class of com-pounds, which represent inevitable alternative to well-knownchloro analogues when substitution reactions with weak nucleo-philes are conducted on a-halo carbon of (a-haloalkyl)boronic es-ters. Therefore, we believe that our study provides a valuablecontribution to the chemistry of (a-haloalkyl)boronic esters.

4. Experimental section

4.1. General

Compounds 2aeg and 3aeewere characterized by 1H NMR, 13CNMR spectroscopy and HRMS spectrometry (also for compounds

S.J. Roseblade et al. / Tetrahedron 70 (2014) 2654e26602658

3feg). NMR spectra were recorded on a Bruker Avance III 500spectrometer and Varian VNMRS 400 spectrometer (500 or400 MHz for 1H NMR and 125 or 100 MHz for 13C NMR). Chemicalshifts were reported in d parts per million referenced to TMS as aninternal standard. 13C NMR chemical shifts of b-carbon atoms incompounds 2 [(Bpin)(Br)Ca]Cb(H)(R3)] were marked bold in thecharacterization section for each compound. High-resolution massspectra (HRMS) were acquired on an Agilent 6224 accurate massTOF LC/MS system. The chromatographic and optical purity ofproducts 3aeg was determined by gas chromatography on anAgilent 6890N with a flame ionisation detector. Retention times foreluting peaks of compounds 2aeg, rac-3aeg, e1-3aeg, e2-3aegand 4aeg are reported. The sign of optical rotationwas determinedon Perkin Elmer 341 series polarimeter. IR spectra were taken withThermo Nicolet Nexus FTIR spectrometer and only noteworthyabsorptions were listed. Melting points were determined withMettler Toledo DSC822e apparatus (heating rate 10 �C/min) andwere referred to as onset values and peak values. Compounds 3aeeare stable, if kept in the freezer (below �10 �C), for at least 4months. At ambient temperature the compounds 3aee decom-posed completely in approximately one year time.

All chemicals and solvents were purchased from commercialsources andwere usedwithout further purification. Anhydrous THFand CH2Cl2 were obtained from SigmaeAldrich. Starting material1b was purchased from the commercial source. Other startingmaterials 1a and 1ceg as well as standards of de-brominatedproducts 4aeg were prepared according to the literatureprocedures.15a

Flash chromatography was performed using Biotage SP1� sys-tem on Biotage� SNAP Cartridges.

Research samples of ligands L2eL3were supplied by prof. Pfaltz,ligands L5eL6 by prof. Mazet, ligands L7eL8 were procured atStrem Chemicals Inc. and ligand L9was purchased at Solvias. Otherligands and catalyst precursors were supplied by Johnson Matthey.All the ligands and catalyst precursors were stored under inertatmosphere prior to use.

4.2. General procedure for the preparation of (1-bromo-1-alkenyl)boronic esters 2aeg

A suspension of Cp2Zr(H)Cl (1.1 equiv) in dry THF was stirredat room temperature under argon atmosphere followed by ad-dition of 0.5 M solution of 1aeg (1.0 equiv) in dry THF. The re-action mixture was stirred for 1 h, resulting in a clear colouredsolution. Addition of N-bromosuccinimide (1.1 equiv) in situ ledto the alternation of the colour of the solution. The obtainedmixture was stirred further at room temperature for 1 h. After-wards, the solvent was removed under reduced pressure, and theproduct was extracted from the residue with n-hexane(5�20 mL). After removal of solvent under reduced pressure, theresidue was purified by Kugelrohr distillation and if needed fur-ther by flash chromatography (silica gel, n-hexane/MTBE, MTBEgradient 2e10%).

4.2.1. 2-(1-Bromo-3-methylbut-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2a). The product was isolated as a light brown oil,yield 67%. nmax(KBr) 2978, 2869, 1614, 1408, 1333, 1321, 1141, 971,854, 699 cm�1; 1H NMR (500 MHz, CDCl3): d 0.99 (6H, d, J¼7.4 Hz),1.30 (12H, s), 2.99 (1H, m), 6.65 (1H, d, J¼10.2 Hz); 13C NMR(125 MHz, CDCl3): d 22.6, 24.7, 31.7, 84.4, 159.3; HRMS (ESI):[MþH]þ, found: 274.0845 C11H21

10BBrO2 requires 274.0849.

4.2.2. 2-(1-Bromovinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(2b). The product was isolated in amixturewith 2-(2-bromovinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2b0) in ratio 2b:2b0¼2:1as a colourless oil, yield 33%. nmax(KBr) 2980, 1610, 1586, 1406, 1341,

1144, 1084, 845, 672 cm�1; 1H NMR (500 MHz, CDCl3): d 1.27 (12H,s, 2b0), 1.32 (12H, s), 6.29 (1H, d, J¼15.1 Hz, 2b0), 6.40 (1H, s), 6.67(1H, s), 7.17 (1H, d, J¼15.1 Hz, 2b0); 13C NMR (125 MHz, CDCl3):d 24.7, 83.7 (2b0), 85.1, 126.9 (2b0), 134.8; HRMS (ESI): [MþH]þ,found: 232.0379 C8H14

10BBrO2 requires 232.0377.

4.2.3. 2-(1-Bromoprop-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2c). The product was isolated as a greasy whitesolid, yield 47%. Mp¼49.7 �C (onset), 53.1 �C (peak); nmax(KBr) 3439,2979, 2934, 1616, 1323, 1255, 1145, 851, 675 cm�1; 1H NMR(500 MHz, CDCl3): d 1.32 (12H, s), 1.91 (3H, d, J¼7.4 Hz), 6.92 (1H, t,J¼8.3 Hz); 13C NMR (125 MHz, CDCl3): d 18.2, 24.7, 84.4, 149.8;HRMS (ESI): [MþH]þ, found: 246.0529 C9H17

10BBrO2 requires246.0536.

4.2.4. 2-(1-Bromopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2d). The product was isolated as light brown oil,yield 56%. nmax(KBr) 2979, 2873, 1616, 1407, 1327, 1144, 966, 850,676 cm�1; 1H NMR (500 MHz, CDCl3): d 0.91 (3H, t, J¼7.4 Hz), 1.31(12H, s), 1.43 (2H, sext, J¼7.2 Hz), 2.32 (2H, q, J¼7.5 Hz), 6.84 (1H, t,J¼8.2 Hz); 13C NMR (125 MHz, CDCl3): d 13.5, 22.2, 24.7, 34.1, 84.4,152.8; HRMS (ESI): [MþH]þ, found: 274.0848 C11H21

10BBrO2 re-quires 274.0849.

4.2.5. 2-(1-Bromo-2-cyclohexylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2e). The product was isolated as a light brown solid,yield 53%. Mp¼58.0 �C (onset), 61.3 �C (peak); nmax(KBr) 3439, 2974,2920, 2844, 1612, 1452, 1140, 885, 698 cm�1; 1H NMR (500 MHz,CDCl3): d 1.13 (4H, m), 1.30 (12H, s), 1.67 (6H, m), 2.66 (1H, m), 6.68(1H, d, J¼10.2 Hz); 13C NMR (125 MHz, CDCl3): d 24.7, 25.6, 25.8,32.9, 41.2, 84.4, 157.7; HRMS (ESI): [MþH]þ, found: 314.1161C14H25

10BBrO2 requires 314.1162.

4.2.6. 2-(1-Bromo-2-phenylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2f). The product was isolated as a light brown oil,yield 43%. nmax(KBr) 3059, 2979, 1617, 1390, 1327, 1242, 1140, 967,852, 695 cm�1; 1H NMR (500 MHz, CDCl3): d 1.32 (12H, s), 7.31 (3H,m), 7.35 (2H, m), 7.65 (1H, s); 13C NMR (125 MHz, CDCl3): d 24.4,84.7, 127.7, 128.25, 128.3, 136.8, 145.6; HRMS (ESI): [MþH]þ, found:308.0692 C14H19

10BBrO2 requires 308.0692.

4.2.7. 2-(1-Bromo-2-(4-fluorophenyl)vinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2g). The product was isolated as a slightlyyellow solid, yield 32%. Mp¼66.6 �C (onset), 72.7 �C (peak);nmax(KBr) 3439, 2980, 1600, 1508, 1242, 1139, 838, 663 cm�1; 1HNMR (500 MHz, CDCl3): d 1.30 (12H, s), 6.99 (2H, m), 7.34 (2H, m),7.61 (1H, s); 13C NMR (125 MHz, CDCl3): d 24.4, 84.8, 115.1(JCF¼19.2 Hz), 129.6 (JCF¼8.3 Hz), 133.0, 144.7, 161.7 (JCF¼247.2 Hz);HRMS (ESI): [MþH]þ, found: 326.0600 C14H18

10BBrO2 requires326.0598.

4.3. Hydrogenation of (1-bromo-1-alkenyl)boronic esters2aee to (a-bromoalkyl)boronic esters 3aee

4.3.1. 2-(1-Bromo-3-methylbutyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3a). Substrate 2a (28 mg, 0.1 mmol) and[Ir(COD)(L8b)]BArF (17mg, 0.01mmol)wereweighed into a glass vialand purged with nitrogen. Dichloromethane (3 mL) was added byinjection and the reaction mixture was purged with nitrogen andhydrogen (five times) with slow stirring. The reaction was heated to50 �C under 30 bar of hydrogenwith stirring for 18 h. The systemwasvented. The reaction crude was analyzed by GC, showing full con-version to give 8% of 4a and 92% of 3a (60% ee). Catalyst residue wasremoved by rapid filtration of the crude reaction mixture througha pipette full of silica gel, eluting with 20:1 isohexane/EtOAc. Theproductwas isolated as a colourless oil in 65e70%yield,with 5%of4a.

S.J. Roseblade et al. / Tetrahedron 70 (2014) 2654e2660 2659

Chromatographic purity was determined by GC method under thefollowing conditions: Chrompack Capillary Column CP-Chirasil-DexCB, 25 m�0.25 mm�0.25 mm; detector, 250 �C; injection, 250 �C;carriergas, helium; carrier gas rate:1.5mL/min; columntemperature:120 �C for20min; total run time20min.Retention times:2a¼7.3min;3a¼8.0min;4a¼2.9min.Chiral puritywasdeterminedbyGCmethodunder the following conditions: Chrompack Capillary Column CP-Chirasil-Dex CB, 25 m�0.25 mm�0.25 mm; detector, 250 �C; in-jection, 250 �C; carrier gas, helium; carrier gas rate: 1.5 mL/min;column temperature: 80 �C for 80 min; total run time 80 min. Re-tention times: e1-3a¼61.9 min; e2-3b¼63.3 min. nmax(KBr) 3439,2958, 2870, 1731, 1616, 1382, 1215, 1139, 968, 728 cm�1; 1H NMR(400 MHz, CDCl3): 0.91 (3H, d, J¼6.4 Hz), 0.94 (3H, d, J¼6.4 Hz), 1.30(12H, s), 1.70 (1H, m), 1.85 (2H, m), 3.40 (1H, t, J¼8.0 Hz); 13C NMR(100 MHz, CDCl3): d 21.4, 22.6, 24.4, 27.2, 42.6, 84.1; HRMS (ESI):[MþH]þ, found: 276.1001 C11H22

11BBrO2 requires 276.1005.

4.3.2. 2-(1-Bromoethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(3b). A mixture of 2b and 2-bromovinyl boronic ester¼2:1 (23 mg,0.1 mmol) and [Ir(COD)(L8b)]BArF (17 mg, 0.01 mmol) wereweighed into a glass reaction vial, placed in a Biotage Endeavour,and purged with nitrogen. Dichloromethane (3 mL) was added byinjection and the reaction mixture was purged with nitrogen andhydrogen (five times) with slow stirring. The reaction was heatedto 50 �C under 30 bar of hydrogen with stirring for 18 h. Thesystem was vented. The reaction crude was analyzed by GC,showing full conversion to give 5% of 4b, 86% of 3b (67% ee) and 9%of other side-products. Catalyst residue was removed by rapidfiltration of the crude reaction mixture through a pipette full ofsilica gel, eluting with 20:1 isohexane/EtOAc. The product wasisolated as a colourless oil in 50% yield, with 5% of 4b. Chromato-graphic and chiral purity were determined by GC method underthe following conditions: Chrompack Capillary Column CP-Chirasil-Dex CB, 25 m�0.25 mm�0.25 mm; detector, 250 �C; in-jection, 250 �C; carrier gas, helium; carrier gas rate: 2.0 mL/min;column temperature: 85 �C for 20 min; total run time 20 min.Retention times: 2b¼6.6 min; e1-3b¼6.5 min; e2-3b¼6.9 min;4b¼2.3 min 1H NMR (400 MHz, CDCl3): 1.34 (12H, s), 1.72 (3H, d,J¼8.0 Hz), 3.45 (1H, q, J¼8.0 Hz); 13C NMR (100 MHz, CDCl3):d 20.6, 24.5, 84.3; HRMS (ESI): [MþH]þ, found: 236.1281C8H16

11BBrO2 requires 236.1281. This is a known compound withspectroscopic and physical properties consistent with those re-ported in the literature.12

4.3.3. 2-(1-Bromopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(3c). Substrate 2c (12 mg, 0.05 mmol) and [Ir(COD)(L8b)]BArF(9 mg, 0.005 mmol) were weighed into a glass vial and purgedwith nitrogen. Dichloromethane (3 mL) was added by injectionand the reaction mixture was purged with nitrogen and hydrogen(five times) with slow stirring. The reaction was heated to 50 �Cunder 30 bar of hydrogen with stirring for 18 h. The system wasvented. The reaction crude was analyzed by GC, showing fullconversion to give 9% of 4c and 91% of 3c (64% ee). Catalyst residuewas removed by rapid filtration of the crude reaction mixturethrough a pipette full of silica gel, eluting with 20:1 isohexane/EtOAc. The product was isolated as a colourless oil in 65e70%yield, with 5% of 4c. Chromatographic and chiral purity weredetermined by GC method under the following conditions:Chrompack Capillary Column CP-Chirasil-Dex CB,25 m�0.25 mm�0.25 mm; detector, 250 �C; injection, 250 �C;carrier gas, helium; carrier gas rate: 1.5 mL/min; column tem-perature: 100 �C for 20 min; total run time 20 min. Retentiontimes: 2c¼12.1 min; e1-3c¼10.0 min; e2-3c¼10.4 min;4c¼2.6 min nmax(KBr) 2978, 2876, 1611, 1373, 1278, 1130, 968,668 cm-1; 1H NMR (400 MHz, CDCl3): 1.04 (3H, t, J¼7.2 Hz), 1.30(12H, s), 1.95 (2H, m), 3.29 (1H, t, J¼7.6 Hz); 13C NMR (100 MHz,

CDCl3): d 13.4, 24.5, 27.5, 84.2; HRMS (ESI): [MþH]þ, found:248.0699 C9H18

11BBrO2 requires 248.0692.

4.3.4. 2-(1-Bromopentyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(3d). Substrate 2d (28 mg, 0.1 mmol) and [Ir(COD)(L8b)]BArF(17 mg, 0.01 mmol) were weighed into a glass vial and purged withnitrogen. Dichloromethane (3 mL) was added by injection and thereaction mixture was purged with nitrogen and hydrogen (fivetimes) with slow stirring. The reaction was heated to 50 �C under30 bar of hydrogenwith stirring for 18h. The systemwas vented. Thereaction crude was analyzed by GC, showing full conversion to give6% of 4d and 94% of 3d (64% ee). Catalyst residue was removed byrapidfiltration of the crude reactionmixture through apipette full ofsilica gel, eluting with 20:1 isohexane/EtOAc. The product was iso-lated as a colourless oil in 65e70% yield, with 7% of 4d. Chromato-graphic purity was determined by GC method under the followingconditions: Chrompack Capillary Column FS-Lipodex-E,25 m�0.25 mm�0.25 mm; detector, 250 �C; injection, 250 �C; car-rier gas, helium; carrier gas rate: 1.5 mL/min; column temperature:110 �C for 10 min; total run time 10 min. Retention times:2d¼7.7min; 3d¼7.0min; 4d¼1.9min. Chiral puritywas determinedbyGCmethod under the following conditions: Chrompack CapillaryColumn CP-Chirasil-Dex CB, 25 m�0.25 mm�0.25 mm; detector,250 �C; injection, 250 �C; carrier gas, helium; carrier gas rate: 1.5mL/min; column temperature: 100 �C for 40min; total run time 40min.Retention times: e1-3d¼25.9 min; e2-3d¼26.9 min. 1H NMR(400 MHz, CDCl3): 0.92 (3H, t, J¼7.2 Hz), 1.30 (12H, s), 1.35 (4H, m),1.92 (2H, q, J¼7.2 Hz), 3.33 (1H, t, J¼8.0 Hz); 13C NMR (100 MHz,CDCl3): d 14.0, 22.2, 24.5, 31.0, 33.8, 84.2; This is a known compoundwith spectroscopic and physical properties consistent with thosereported in the literature.14a

4.3.5. 2-(1-Bromo2-cyclohexylethyl)-4,4,5,5-tetramethyl-1,3,2-diox-aborolane (3e). Substrate 2e (31 mg, 0.1 mmol) and [Ir(COD)(L2)]BArF (15 mg, 0.01 mmol) were weighed into a glass vial and purgedwith nitrogen. Dichloromethane (3 mL) was added by injection andthe reaction mixture was purged with nitrogen and hydrogen (fivetimes) with slow stirring. The reaction was heated to 50 �C under30 bar of hydrogen with stirring for 18 h. The system was vented.The reaction crude was analyzed by GC, showing 95% conversion,7% of 4e and 88% of 3e (2% ee). Catalyst residue was removed byrapid filtration of the crude reaction mixture through a pipette fullof silica gel, eluting with 20:1 isohexane/EtOAc. The product 3ewasisolated as a colourless oil in 65e70% yield, with 5% of 4e. Chro-matographic purity was determined by GC method under the fol-lowing conditions: Chrompack Capillary Column CP-Chirasil-DexCB, 25 m�0.25 mm�0.25 mm; detector, 250 �C; injection, 250 �C;carrier gas, helium; carrier gas rate: 2.0 mL/min; column temper-ature: 160 �C for 20 min; total run time 20 min. Retention times:2e¼6.5 min; 3e¼7.1 min; 4e¼2.9 min. Chiral purity was de-termined by GC method under the following conditions: Chrom-pack Capillary Column CP-Chirasil-GammaDex 225,25 m�0.25 mm�0.25 mm; detector, 250 �C; injection, 250 �C; car-rier gas, helium; carrier gas rate: 2.0 mL/min; column temperature:120 �C for 150 min; total run time 150 min. Retention times: e1-3e¼127.3 min; e2-3e¼128.8 min. nmax(KBr) 3439, 2924, 2852, 1725,1581, 1385, 1246, 1139, 849, 681 cm-1; 1H NMR (400 MHz, CDCl3):0.87 (3H, m),1.10e1.35 (15H, m),1.65 (8H, m), 3.44 (1H, t, J¼8.0 Hz);13C NMR (100 MHz, CDCl3): d 24.4, 26.1, 26.5, 26.8, 32.2, 33.9, 36.7,41.2, 84.1; HRMS (ESI): [MþH]þ, found: 316.1307 C14H27

10BBrO2requires 316.1318.

Acknowledgements

We thank A. Veskovi�c, S. Bori�sek and D. Orki�c for the technicalassistance in some experimental work; P. Skelton (Univ. of

S.J. Roseblade et al. / Tetrahedron 70 (2014) 2654e26602660

Cambridge), Dr. D. Urankar and Prof. dr. J. Ko�smrlj (Univ. of Ljuljana)for HRMS analysis; Dr. M. �Crnugelj for the acquisition of some NMRspectra, J. Fabris for acquisition of optical rotation data, IR and DSCspectra and P. Drnov�sek as well as A. Zanotti-Gerosa for the givensupport. We also thank Prof. A. Pfaltz and Prof. C. Mazet who sup-plied some of the catalyst samples.

Supplementary data

Supplementary data contains full catalyst screening details,copies of 1H NMR spectra, 13C NMR spectra and GC chromatograms.Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.tet.2014.02.065.

References and notes

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25. For the preparation and application of SimplePHOX ligands, see: Smidt, S. P.;Menges, F.; Pfaltz, A. Org. Lett. 2004, 6, 2023e2026.

26. For the synthesis and application of ThrePHOX phosphiniteeoxazoline ligands,see: (a) Blankenstein, J.; Pfaltz, A. Angew. Chem., Int. Ed. 2001, 40, 4445e4447;(b) Menges, F.; Pfaltz, A. Adv. Synth. Catal. 2002, 344, 40e44.

27. For the synthesis and application of phosphanyl oxazoline ligands, see: (a)Mantilli, L.; Mazet, C. Chem. Commun. 2010, 445e447; (b) Schrems, M. G.;Neumann, E.; Pfaltz, A. Angew. Chem., Int. Ed. 2007, 46, 8274e8276 and refer-ences cited therein; (c) Porte, A. M.; Reibenspies, J.; Burgess, K. J. Am. Chem. Soc.1998, 120, 9180e9187.

28. For the synthesis and application of chiral spiro phosphine-oxazoline ligands,see: Zhu, S.-F.; Xie, J.-B.; Zhang, Y.-Z.; Li, S.; Zhou, Q.-L. J. Am. Chem. Soc. 2006,128, 12886e12891.

29. For the synthesis and application of NeoPHOX ligands, see: Schrems, M. G.;Pfaltz, A. Chem. Commun. 2009, 6210e6212.

30. Hall, D. G. In Boronic Acids-preparation and Applications in Organic Synthesis andMedicine; Hall, D. G., Ed.; Wiley-VCH: Weinheim, Germany, 2005; pp 6e7;(Chapter 1).

31. Hedberg, C.; K€allstr€om, K.; Brandt, P.; Hansen, L. K.; Andersson, P. G. J. Am. Chem.Soc. 2006, 128, 2995e3001.